Mechanisms of Macrophage Mediated Chemoprotection in Breast Cancer

描述(申请人提供)：这个项目旨在阐明巨噬细胞介导的化学保护在乳腺癌中的机制。我们发现紫杉醇(Taxol)治疗后，患者和动物模型中原发乳腺肿瘤中肿瘤相关巨噬细胞(TAMs)和组织蛋白酶水平增加。表达组织蛋白酶的巨噬细胞在共培养中对紫杉醇诱导的肿瘤细胞死亡具有保护作用，这种作用可被组织蛋白酶抑制完全逆转，并部分由组织蛋白酶B和组织蛋白酶S介导。巨噬细胞也被发现对附加化疗药物，特别是依托泊苷和阿霉素诱导的肿瘤细胞死亡具有保护作用。体内联合应用紫杉醇和组织蛋白酶抑制显著增强了对原发和转移肿瘤的疗效，支持了这一效应的治疗相关性。这一应用的主要假设是，巨噬细胞分泌的组织蛋白通过其蛋白分解活性直接调节肿瘤细胞的生存信号，迅速诱导化疗耐药状态。该应用的目的是确定微环境化疗耐药适应的分子机制，并开发阻断肿瘤化学保护的治疗策略。第一个目标是确定巨噬细胞分泌的组织蛋白对化疗诱导的肿瘤细胞死亡的中介保护的必要性和充分性。第二个目标是确定受组织蛋白酶活性调控的肿瘤细胞生存信号通路(S)，并确定决定这种化学保护机制敏感性的基因组变化。第三个目标是评估急性或增强的组织酶抑制剂治疗是否会导致体内化疗反应的更大改善，并确定在辅助治疗方案中添加组织酶抑制剂的疗效。这项工作的意义超越了乳腺癌的微环境，通过阐明分子机制，我们希望确定巨噬细胞和组织蛋白酶导致治疗失败的其他癌症类型和器官部位。因此，我们打算进一步证明针对肿瘤及其微环境的综合治疗靶点的重要性。

DESCRIPTION (provided by applicant): This project aims to elucidate the mechanisms of macrophage-mediated chemoprotection in breast cancer. We have found that in response to paclitaxel (Taxol) treatment there is an increase in tumor-associated macrophages (TAMs) and cathepsin protease levels in primary breast tumors in patients and in animal models. Cathepsin-expressing macrophages protected against Taxol-induced tumor cell death in co-culture, an effect fully reversed by cathepsin inhibition and mediated partially by cathepsins B and S. Macrophages were also found to protect against tumor cell death induced by additional chemotherapeutics, specifically etoposide and doxorubicin. Combining Taxol with cathepsin inhibition in vivo significantly enhanced efficacy against primary and metastatic tumors, supporting the therapeutic relevance of this effect. The main hypothesis of this application is that macrophage-secreted cathepsins directly modulate tumor cell survival signaling through their proteolytic activity, rapidly inducing a chemoresistant state. The objectives of this application are to identify the molecular mechanisms underlying microenvironmental chemoresistance adaptations, and develop therapeutic strategies to block chemoprotection in tumors. The first aim will be to determine the necessity and sufficiency of macrophage-secreted cathepsins to mediate protection against chemotherapy-induced tumor cell death. The second aim will be to identify the tumor cell survival signaling pathway(s) modulated by cathepsin activity, and determine the genomic alterations that dictate sensitivity to this mechanism of chemoprotection. The third aim will be to evaluate whether acute or enhanced cathepsin inhibitor treatment will result in a greater improvement in chemotherapeutic response in vivo, and determine the efficacy of adding cathepsin inhibitors to adjuvant treatment regimens. The implications of this work extend beyond the breast tumor microenvironment and through the elucidation of molecular mechanism we hope to identify other cancer types and organ sites where macrophages and cathepsin proteases contribute to treatment failure. We thereby intend to further demonstrate the critical importance of integrated therapeutic targeting of the tumor and its microenvironment.